Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Harald M.H.G. Albers, Anping Dong, Laurens A. Van Meeteren, David A. Egan, Manjula Sunkara, Erica W. Van Tilburg, Karianne Schuurman, Olaf Van Tellingen, Andrew J. Morris, Susan S. Smyth, Wouter H. Moolenaar, Huib Ovaa

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC50 ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.

Original languageEnglish
Pages (from-to)7257-7262
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number16
DOIs
StatePublished - Apr 20 2010

Keywords

  • High-throughput screening
  • Lysophosphatidic acid
  • Lysophospholipase D
  • Phosphodiesterase
  • Small-molecule inhibitor

ASJC Scopus subject areas

  • General

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